Engineering nano-clustered multivalent agonists to cross-link TNF receptors for cancer therapy

作     者：Yue Zhang Gui Zhao Yi-Fang Chen Shi-Kun Zhou Yue Wang Yi-Qun Sun Song Shen Cong-Fei Xu Jun Wang 

作者机构：School of Biomedical Sciences and EngineeringSouth China University of TechnologyGuangzhou International CampusGuangzhouP.R.China National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhouP.R.China Guangdong Provincial Key Laboratory of Biomedical EngineeringSouth China University of TechnologyGuangzhouP.R.China Key Laboratory of Biomedical Materials and Engineering of the Ministry of EducationSouth China University of TechnologyGuangzhouP.R.China 

出 版 物：《Aggregate》 (聚集体（英文）)

年 卷 期：2023年第4卷第6期

页      面：209-220页

学科分类：1002[医学-临床医学] 0805[工学-材料科学与工程（可授工学、理学学位）] 100214[医学-肿瘤学] 0703[理学-化学] 10[医学] 

基　　金：National Key R&D Program of China,Grant/Award Number:2022YFB3808100 National Natural Science Foundation of China,Grant/Award Numbers:32271442,52130301,82072048 Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2022B1515020025 Science and Technology Program of Guangzhou,China,Grant/Award Number:202103030004 Fundamental Research Funds for the Central Universities,Grant/Award Number:2022ZYGXZR102。 

主　　题：antibody cancer therapy drug delivery nanoparticle TNFR 

摘      要：Tumor necrosis factor receptors(TNFRs)are promising targets for cancer therapy.However,activating their downstream signaling requires cross-linking of TNFRs.Herein,to devise strong agonists of TNFRs,ligands targeting TNFRs,such as OX40L and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL),were fused with a multivalent protein scaffold(MV)to prepare multivalent agonists for cross-linking TNFRs.The nano-clustered multivalent-OX40L(MV-OX40L)and MV-TRAIL could promote T cell activation and directly induce tumor cell apoptosis.Moreover,to develop a universal nano-adaptor for the rapid preparation of multivalent agonists of different TNFRs,the Fc receptor that could immobilize antibodies was fused with MV to prepare MV-FcR,which could multimerize commercial agonist antibodies targeting TNFRs,such as anti-OX40 antibody(αOX40).Simply incubatingαOX40 with MV-FcR could prepare MV-αOX40 to enhance its antitumor efficacy.In addition,MV-FcR could multimerize with other therapeutic antibodies,such as anti-PD-L1 antibody,to enhance their valency.This study provides a promising strategy for engineering multivalent antitumor protein drugs.